Incidence of Pediatric Perforated Appendicitis during the COVID-19 Pandemic; a Systematic Review and Meta-Analysis

Introduction: COVID-19 has affected the pattern of referral to medical centers and quarantine against COVID-19 might delay referral and management of surgical emergencies. This study aimed to compare the pooled event rate of pediatric perforated appendicitis before and during the COVID-19 pandemic. Methods: This was a systematic review and meta-analysis study based on the PRISMA guidelines. Scopus, Web of Sciences, and PubMed databases were searched for studies reporting the rate of perforated appendicitis based on the post-appendectomy observations or imaging methods. The Egger bias test and funnel plot were used to detect and depict publication bias. Statistical analysis was performed in Comprehensive Meta-analysis package version 3. Results: Twelve studies were eligible for inclusion in our study. The pooled prevalence of pediatric perforated appendicitis in the pre-COVID era was 28.5% (CI95%: 28.3 to 28.7%) with a heterogeneity of 99%. In the COVID era, the event rate proportion was 39.4% (CI95%: 36.6 to 42.3%) with a heterogeneity of 99%. There was a significant difference in the subgroup analysis within the pre-COVID and COVID era (P<0.001), showing a higher perforation rate in the COVID era. Conclusion: Our study showed that during the COVID-19 pandemic, the rate of perforated appendicitis has significantly increased in comparison to before the COVID-19 pandemic.


Introduction
Diagnosis and decision-making about some diseases like abdominal pain can be challenging for physicians (1). In surgery, the most common cause of abdominal surgery is acute appendicitis. Appendicitis is a surgical emergency and a common disease that can present with a variety of symptoms (2). The manifestations of this disease overlap with several other medical conditions. Sometimes the complexities and differences in the way it occurs can lead even the most experienced physicians to mistake it for other conditions (3). In some cases, especially in children, the symptoms may be deceptive and difficult to diagnose, and on the other hand, prolongation of the disease may be life-threatening or cause severe complications (4). Therefore, correct and timely diagnosis of the disease requires experience and special skills. Lack of ability of children to give an accurate history, delayed diagnosis by parents and physicians, and the presence of nonspecific gastrointestinal disorders are other causes of late diagnosis of acute appendicitis in children (5,6). Appendicitis in pediatric cases is more likely to rupture, and due to the lack of omentum growth in children, peritonitis is more likely to occur and complications are more common (7). In children under 5 years of age, both the diagnosis of acute appendicitis and the risk of appendix rupture is higher (8). Currently, since COVID-19 has emerged as a pandemic all around the world, some concerns have been raised about the management of surgical emergencies in pediatric cases. COVID-19 has a variety of clinical manifestations, including abdominal pain, which can make it difficult for physicians to differentiate acute appendicitis, and as a result, the risk of perforation of the appendix increases (9). Additionally, the quarantine imposed during the COVID-19 epidemic, as well as the refusal of parents and children to visit hospitals out of fear of getting infected with the virus, could have resulted in the increased rate of perforated appendicitis or its complications. This study aimed to compare the pooled event rate of pediatric perforated appendicitis before and during the COVID-19 pandemic.

Study design and setting
This systematic review and meta-analysis study was done based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We quarried Scopus, Web of Sciences, and PubMed databases for studies irrespective of the study time, limiting results to English articles, cross-sectional and retrospective or prospective studies using the keywords of Appendicitis, Acute Appendicitis, Perforated, Perforation, Appendix, Appendectomy, Children, and Pediatric. The following search strategy was Studies reporting the rate of perforated appendicitis based on the post-appendectomy observations or imaging methods were considered eligible to be included in our study if reporting them in the pediatric age group (under 18 years old).

Quality assessment
The Newcastle-Ottawa Quality Assessment Scale (NOS), which was adapted to measure characteristics of quality relevant to population-based studies of incidence, was used to assess the studies' quality (10). Studies having a low possibility of bias were included.

Measured outcome
Our study outcome was comparing the proportion of perforated appendicitis within two time periods of the Post COVID-19 era (from December 2019) and pre COVID-19 era (before December 2019). Studies were included from 1995 to 2021.

Statistical analysis
The Cochran Q test (two-test for heterogeneity) was used to assess the heterogeneity of the studies. I 2 and its 95% confidence interval (CI) were used to calculate the percentage of total heterogeneity to total variability. A Q test with a P<0.1 or an I 2 greater than 60% was considered to show significant statistical heterogeneity. Random-effects models with double arcsine transformations were used. A 2-sided P<05 was considered statistically significant, regardless of the I 2 statistic. In order to assess the significant difference in proportions between groups in each analysis, we calculated the inter-group P-value; when there was a significant difference, we ran pairwise comparisons and adjusted the level when necessary. A funnel plot was used to depict publication bias. The Egger bias test and the Begg-Mazumdar rank correlation Kendall 2 statistic were used to detect asymmetry. Statistical analysis was performed in Comprehensive Meta-analysis package version 3 and bias possibility was visualized using Review Manager Version 5.4.1.

Results
As shown in figure 1, there were 6234 articles found in the initial search, conducted by two independent researchers, from which 1745 duplicated articles were removed. Then based on the abstracts, unrelated articles, including review articles, interventional and case-control studies, and studies only on the adult population were excluded from the study. Also, articles whose abstract or main text was not available were excluded. Finally, 278 potentially related articles were listed for full text review. Twelve studies were eligible to be included in our study. A checklist including the name of the researcher, article title, year and place of study, sample size, and prevalence of perforated appendicitis was used to collect data (table 1). 8 studies were conducted in COVID era, also containing datasets of before COVID. 9 studies were performed in US, one in Pakistan, one in Germany, and one in UK. The largest sample size belonged to Cheong LH et al. study with 120117 participants.

Discussion
Our study showed that there has been an increase in the rate of perforated appendicitis during the COVID-19 pandemic in comparison to before the COVID-19 pandemic. Difficulty diagnosing the disease usually delays the start of treatment and in many cases leads to perforation. While delayed referral to a medical center could also be a potential factor leading to perforation; COVID-19 pandemic has decreased public referral to hospitals due to fear of infection (22). Due to the high mortality rate, appendicitis is on the list of important diseases in children. Considering the rapid progression of this disease in children, the need for timely diagnosis of the disease in order to prevent side effects is emphasized by all surgeons. Despite the existence of radiological techniques for diagnosing appendicitis, it is still difficult to diagnose acute appendicitis. Additionally, physicians should also be aware of COVID-19's gastrointestinal symptoms that might mimic acute abdomen symptoms (23,24). In case of ruptured appendicitis, the risk of complications increases. Imposing unnecessary surgery can also cause complications such as intestinal adhesions (25). Our study indicated that during the COVID-19 pandemic, the rate of perforated appendicitis has significantly increased in comparison to before the COVID-19 pandemic. Additionally, other studies have shown that even before the pandemic, there were seasonal variations in acute appendicitis cases (26) and racial factors might also be affecting the disease prevalence (8). Research has shown that even in one country, the prevalence of acute appendicitis might change over the years (27). Following the outbreak of COVID-19 and the responsibility of hos-pitals to provide services to patients with COVID-19, the provision of medical services to other patients was largely shut down and only emergencies continued; that might have led to missed cases of some urgent diseases including acute abdomen. These patients will suffer if left untreated. Therefore, hospitals must be prepared to accept non-COVID-19 patients. Based on Ojetti et al. study, this issue is not limited to appendicitis. The sharp drop in ED visits during the pandemic might be attributed to fear of the virus, implying that individuals with significant conditions did not seek medical help. Worrying statistics emerged, in particular, about a decrease in cardiology and neurology admissions. Those patients put off seeking medical help out of fear of being exposed to COVID-19, resulting in increased morbidity and mortality (28). We recommend Global community training for dealing with emergencies during the pandemic so that time-critical medical situations are not neglected.

Limitations
There are many factors affecting the prevalence of perforated appendicitis, such as ethnicity, seasonal variation, and the medical centers' approaches to acute abdomen, which were not considered in our study.

Conclusion
Our study showed that the COVID-19 pandemic might have led to an increase in the rate of perforated appendicitis in comparison to the before COVID-19 pandemic. One of the serious health concerns during the pandemic is the state of people's health due to urgent non-COVID-19 diseases, which covers a wide range of patients including acute abdomen cases.

Acknowledgments
We would like to thank the Clinical Research Development Unit of Peymanieh Educational and Research and Therapeutic Center of Jahrom University of Medical Sciences for providing facilities for this work.

Authors' contribution
GM, MG, NK, MF, and FB conceptualized the study questions and performed revisions. PA, NH, and ER performed the searches. GM, MG, SA, ME, FM, and RF conducted the statistical analyses. Other authors provided the draft of the manuscript.

Ethical Considerations
All ethical principles were considered in this article.